Compounds for synthesizing steroids



United States p hv 2,759,929 v I COMPOUNDS FOR SYNTHESIZING STEROIDS W. Farrar, Webster Groves, Harold Raitelson,

St. Louis, and William S. Knowles, Kirkwood, Mo., as-

signors to Monsanto Chemical Company, St. Louis,

'Mo., a corporation of Delaware I v No Drawing. Application July 23, 1953, Serial No. 369,944 2 Claims. 01. 260-23955 This invention relates to methods and novel compounds of ,v the, cyclopentanodimethylpolyhydrophenanthrene series having a 3-keto group and a double bond in the 4,5 position which compounds are intermediates in proceeding from a 17-forn'1y1-cyclope'nt-1'6-eno-10,13-dimethyl- A -decahydrophenanthren-3-one to a 17-(acyloXyacetyl) 17 hydroxy-cyclopentano-IO,13-dimethy1-A dodecahydrophenanthren-3,11dione. In particular this invention relates to methods and novel compounds useful in the preparation of acyl derivatives of 3,11,20- triketo-17,2l-dihydroxy-A -pregnene from a 3 keto 17 formyl-M- -androstatriene.

The sequence of steps or series of reactions proceeding from a 17 formyl cyclopent-lG-eno-IO, 13-dimetliyl Amt1 )-decahydrophenanthren-3-one to a 17-'(acyloxyacetyl) 17-hydroxycyclopentano-l0,13-dimethyl-M-do- 2,759,929 Patented Aug. 21, 1956 decahydrophenanthren-3Jl-dione essentially comprises (1) epoxidizing a 17-formy1-cyc1opent-16-eno-10,13- dimethyl- A Ldecahydrophenanthren 3 one with an oxygen furnishing agent, (2) converting the formyl group of the 16,17-0Xido compound so formed to a carboxyl group, (3) reacting the carboxylic acid so obtained with an acyl halide forming agent, (4) reacting the resultant acid halide with diazomethane, (5) reacting the diazoketone so formed with a carboxylic acid to form a 17- (acyl0xyacetyl-)-16,17 oxido cyclopentano 10,13-dimethyl M -decahydrophenantl1ren 3 one, (6) reacting" said latter compound with a hydrogen halide, (7) reacting the 16 halo 17-hydroXy-17-(acyloxyacetyl)- cyclopentano 10,13-dimethy1-A -decahydrophenanthren-3-one so formed with a hypohalous acid, (8) oxidizing" the 9,16-dihalo-11,17-dihydroxy-17-(acyloxyacetyl)- cyclopen tano-10,13-dimethyl A dodecahydrophenam thren-B-one with a complex of chromium oxide. and a tertiary amine, (9) de-halogenating the 9,16-dihalo-17- hydroxy l7-(acyloxyacetyl) cyclopentano 10,13 di-. methyl-M-dodecahydrophenanthren-3,ll-dione so as to produce a 17-(acyloxyacetyl)-17-hydroxy-cyclopentano- 10,13-dimethyl-A -dodecahydrophenanthren-3,11 dione. The aforesaid sequence of steps is outlined schematically as follows:

ice

This invention will be described in detail with respect to its preferred embodiment but it is to be understood that such is not limitative of this invention.

The first step in the process of this invention is the epoxidation of a 17-forrnyl-cycopent-16-eno10,l3-dimethyl-A -decahydrophenanthren-3-one to a 16,17- oxido-l7-formyl-cyclopentano-10,l3 dimethyl A decahydrophenanthren-3-one (Compound II) employing an oxygen furnishing agent such as the organic per-acids or hydrogen peroxide in an amount corresponding to approximately one chemical equivalent. The epoxidation is ordinarily carried out by mixing the oxidant and the 17 formyl-cyclopent-l6-eno-l0,13-dirnethyl-A -decahydrophenanthren-3-one together in an organic medium which is non-reactive under the reaction conditions. Suitable media include chloroform, carbon tetrachloride, diethyl ether, glacial acetic acid, methanol, ethanol, isopropanol, and the like. The temperature employed in the epoxidation may vary widely but ordinarly will be in the range of from about -l C. to about 50 C. A convenient reaction-medium when the oxidant is hydrogen peroxide is a low molecular weight alcohol.

As illustrative of the first step of the process of this invention is the following:

Example I To a suitable reaction vessel containing 50 parts by weight (substantially 0.169 mol) of dl-3-keto-17-formyl- M -androstatriene (m. p. 178178.5 C.) dissolved in 4200 parts by weight of methanol maintained at about C. is added approximately 170 parts by weight of sodium carbonate as a 5% aqueous solution followed by a methanol-hydrogen peroxide mix containing approximately 5.7 parts by weight of hydrogen peroxide. The mix so obtained is stirred for about 16 hours at about aqueous layer is acidified and then extracted with chloroform. The chloroform extracts are combined, dried and subjected to vacuum distillation. Upon evaporation of the chloroform there .is obtained a solid residue which upon triturating with diethyl ether yields 35 parts by weight of crystalline dl 3 keto 16,17 oxido-l7-carboxy-A Q androstadiene.

To a solution containing approximately 50 parts by weight of dl 3 keto 16,17 oxido-l7-carboxy-A androstadiene in approximately 4000 parts by weight of 0 C. Thereupon substantially all of the methanol is removed by vacuum distillation and the residue is then taken up with chloroform. The chloroform solution is then washed with water and dried over anhydrous magnesium sulfate. Upon evaporation of the chloroform there is obtained a white solid residue, which upon triturating with diethyl ether yields white crystalline dl-3-keto- 16,l7-oxido-17-formyl-A -androstadiene.

Similarly the individual optically active isomers such as the natural modification of 3-keto-l6,17-oxido-17- forrnyl-A -androstadiene are obtained beginning with the appropriate optically active isomer of 3-keto-17- formyl M androstatriene. The natural modifica- H tion of 3-keto-l6,17-oxido-17-formyl-A -androstadiene is obtained employing the procedure ofExample I but replacing dl-3-keto-17-formyl-A -androstatriene with the dextro-rotatory form of 3-keto-17-formyl- A -androstatriene (melting point 160.5161.5 C.).

The next step in the process of this invention is the conversion of the formyl group, i. e. the substituent in the 17- position, to a carboxy group (Compound III of the schematic diagram). This is readily brought about employing a mild oxidizing agent such as silver oxide, sodium chromate in acetic acid, and the like. As illustrative of the preparation of a 3-keto-16,17-oxido-17-carboxy-A androstadiene is the following:

Example II To an intimate mixture containing approximately 200 parts by weight of dioxane, approximately 192 parts by weight of 2.74 N sodium hydroxide, and approximately 60 added approximately 50 parts by weight of the acid chlohydrophenanthren-3-one.

44.6 parts by weight of silver nitrate is slowly added ap- E proximately 40 parts by weight of dl-3-keto-16,17-oxido-' 17-formyl-A -androstadiene. the addition of the 16,17-oxido compound approximately 200 parts by weight of water and approximately 200 parts by weight of dioxane is added Thereafter the mix is agitated for about one hour and is then filtered. The collected residue is washed with water and th washings combined with the original filtrate. The

with constant agitation.

Upon completion of anhydrous methanol is added sufficient sodium methylate to neutralize the epoxy acid. The methanol is removed by vacuum distillation and to the residue is added and intimately mixed about 450 parts by weight of benzene and about 2.5 parts by weight of pyridine followed by about 250 parts by weight of oxalyl chloride while maintaining the temperature at about 10 C. The mix so obtained is allowed to stand for about 30 minutes, whereupon the mix is subjected to vacuum distillation while maintaining the temperature at about 15 C. The residue-is then taken up with about 500 partsby weight of benzene and again subjected to vacuum distillation at -about 15 C. The residue is taken up with about 250 parts by weight of benzene and filtered. Upon subjecting the filtrate to'vacuum distillation there is obtained the solid acid chloride of dl-3-ketol6,l7-oxido-17-carboxy-A -androstadiene.

.Similarly the individual optically active isomers such as the acid chloride of the natural modification of 3-keto- 16,-17-oxido-17-carboxy-A -androstadiene are obtained from the appropriate optically active isomer.

The next step in the process of this invention is the preparation of the diazoketone (Compound V) by reacting diazomethane with an acid halide of a 16,17-oxido- 17 carboxy cyclopentano-I0,13-dimethyl-A -deca- Ordinarily an excess of two chemical equivalents of diazomethane is employed in converting the acid halide (Compound IV) to the diazoketone (Compound V) and in general the process i carried out in an inert organic solvent such as diethyl ether, benzene, dioxane, toluene, etc., at a temperature in the range of 20 to 40 C. As illustrative of the preparation of the diazoketone is the following:

Example IV To a suitable reaction vessel containing an ether solution containing parts by weight of diazomethane is ride of dl-3-keto-l6,l 7-oxido-17-carboxy-A -androstadiene dissolved in 500 parts by weight of benzene while maintaining the temperature at about 0 C. The mixture so obtained is then agitated for about one hour at about 0 C. The mix is then subjected to vacuum distillation to remove the solvents whereupon there is obtained yellow crystalline dl 3,20 diketo 16,17 oxido-21-diazo- A l -pregnadiene. 701

- as the natural modification of 3,20-diketo-16,17-oxido-2ldiam-A l regnadiene are obtained beginning with the Similarly the individual optically active isomers such acid halide of the appropriate optically active isomer of 3-keto-16,l7 oxido-17-carboxy-A -androstadiene.

The next step in the process of this invention is the forgreases mation of the 17 (acyloxyacetyl) 16,l7-oxide cyclopem tano 10,13 dimethyl A -deeahydrophenanthfefi li one (Compound VI) from the diaioketo'ne (Compound V)" by heating the latter in the presence of a monocarboxylic acid'such as' acetic acid, propionic acid, buty'ric acid, valeric acid, caproic acid, lauric' acid, stearic acid, phenylacetic acid, fl-phenylp'ropionic acid, benzoic'acid', toluic acid, etc., in the presence'where desirable of an inert organic solvent such as benzene, toluene, xylene, dioxane, etc. It is preferred that the carboxylic acid be a fatty acid and preferably one containing from 2 to 4 carbon atoms. As illustrative of this step is the following:

Example V 1 To a suitable reaction vesselcontaining approximately 5000 parts by weight of acetic acid'is added approxiniately SO'parts by weight of a'l-'3,20-diketo-16,17-oxido 2'l-diaio A l-pregnadiene and the mix so obtained heated at about 90-95 C. for about 30 minutes. The resultant is then subjected to' vacuum distillation and the residue so obtained taken up with chloroform. The chloroform solution is then washed with aqueous sodium bicarbonate, then with water and finally dried. Upon removal of the solvent there is obtained solid dl-3,20-diketol6,l7-oxi-do 21acetyloxy-A -pregnadiene in the form ofwhite'crystals.

Similarly theindividual optically active isomers such as the n at'uial modification of 3,20-diketo-16,17-oxido-21- acet'yloxy-Mfl(m-pregnadiene are obtained from the ap-' propriate optically active isomer of 3,20-'diketo'-16,17-oxido-2'l-di'azo-A -pregnadiene.

The next step of the process offthis' invention is the open-.

ingof thepoxide groupin'g byreacting'the 17-.(acy1oxy acetyl)" 16,17 oxido cyclopentano 10,13-din'1th3 1- M decahydfophenanthrenf 3 one (Compound vI)j with 'a'hydrogen, halide such as ,HC1,I-I Br oriHl which results in the forma'tion of a halohydi'in (Compound VII), n'a'mely 16 halo-17-hydroxy17-(acyloxyacetyl)-cyclopentarlo 10,13 dim'ethyl A -decahydrophenanthren-l- This reaction is preferably carried out in an inert organic solvent containingdissolved therein the hydrogen halide reactant and at a temperature in the range'of about -20 C. to about 40 C. As illustrative of this step is the following: 7

Example VI Approximately 4 parts y weight of d l-3,20-dikete-16,

17 oxido 21 acetyloxy-A -pregnadiene is admixed with approximately 3000 parts by'weight of acetic acid and approximately 1000 parts by weight of benzene in a suitable reaction vessel. There'to is added while maintaining the temperature at about 0 C. approximately 80 parts by w eight of a 38% acetic acid. solution of hydrogen bromide andthe mix so obtainedagitated for about 30 minutesat about 0 C. To the mix is then added an equal volume of water and the composite so obtained extracted withseveral small portionsof chloroform. The'chloroform extracts are combined, washed with water anddriedover anhydrous magnesium sulfate. Upon subjecting the so dried solution to vacuum distillation in order to remove the chloroform there ,is obtained white crystalline dl-3,20-diketo-16fi-bromo-17ahydroxy-21acetyloxy-A -pregnadiene.

In a similar fashion but employing hydrogen chloride instead of. hydrogen bromide white crystalline dl-3,20- diketo 16/8 chloro 17cc hydroxy 21 e acetyloxy- Ae l-pregnadiene is obtained from dl-3,20-diketo- 16,1'7-oxido-21acetyloxy-A -pregnadiene Sirnilarly theindividual optically active isomers. such.

as the natural modification of 3,20-diketo-16 8-bromo- 17oi-hydroxy-21acetyloxy-A -pregnadiene tained from the appropriate optically active isomer of 3 ,ZO-dilreto-l 6,17-oxido-2lacetyloxy-A pregnadiene.

Thenext step in t he process of this invention is the reacting of the l6-halo l7-hydroxy compound (Coni pouiid' V11) with a'hypohalous acid to form the"9',16-

are ob;

dihalo- 11,17 dihydroxy 17 (acyloxya'cetyl)' cyan)- pentano 10,13 dimethyl A dodecahydro phenan thren-3-one (Compound VHI). The addition reaction is brought about by mixing a solution of a hypbhalous acid, preferably hypobromousacid, with a solution of a 16 halo 17 hydroxy 17 (acyloxya'cet'yl) cyclopentano 10,13 dimethyl A decahydrophenanthren-3-one at a temperature in the'range of about to 30 C. The 9 -haloand ll-hydroxy substituents'so introduced bear a transrelationship to 'one another, that is one occupies the plane above ring C while the other occupies the plane below ring C, however, itis to be understood that the element of'this invention isn'ot'lim ited to any assumption as to chemical structure but per tains broadly to the 9-halo-l1-hydroxy'addition product of a hypohalous acid and' a ld-halo-l7- hydroxy l7j- (acyloxyacetyl) cyclop'enta'no 10,13 dimethyl- A -decahydrophenanthren fa'-onc (Compound VII). Various solvents which are inert under conditions of'the addition reaction maybe-used in the preparation of the 9-halo-l l-hydroxy addition product(Compound VIII) for example acetone, methyl ethyl ketone, methyl acetate, ethylacetate, tert. butanol, etc.

In'thisstep of the process of this invention it' is preferred that the hypohalous acid employed be hyp t'nla romous acid and such can be prepared in several ways, for example by mixing mercuric oxide with bromine and water and filtering off the mercuric bromide thus formed, or by mixing N-bromoac'etamide with water and tertiary butanol or, preferably, by mixing a solution of N-bromosuccinimide.

CHsC

NBr

CHzC

in a suitable inert organicsolvent, e. g. acct-Quaternary? butanol, with water and a small amount of sulfuric acid;

Where desired, the hypobromous acid solution can be preparedfirst and then mixed with 16-halo-17-hydroxy- 17 (acyloxyacetyl) cyclopentano 10,13-dimethyl-' A -decahydrophenanthren-3 one (Compound VII or, preferably, the hypobromous acid is prepared in the presence of the reactant (i. e. Compound VII) so that parts by weight" of dl-3,20-diketo-16 8-bromo-17a hy: droxy 21 acetyloxy A pregnadiene, substantially 2800 parts by weight of acetone and substantially1200 parts by weight of water ,is added at about "05 C.' ap

proximately 50 parts by weight of 1 N sulfuric acid. To

these cooledland acidified solution is slowly added' a l solution; containing substantially 35 parts by weight 'of N-bromo-succinimide in approximately 360 ,parts' by Upon completion .of the N-bromosuccinimide addition the mix is agitatedfor about 5 hours at about 0-5 G, the bromo-hydrin crystallizes from. At the endof the":

weight of acetone.

the solution during the agitation. agitation period aqueous sodium sulfite is added tofdestroy the excess N-bromo-s'uccinimide'and then the The mix is then filtered and the residue washed first with water, then with acetone and dried. The white crystallineproduct is neutralized with sodium bicarbonate.

In a similar fashion beginning with dl3 ,20diketo 16f!- chloro 17a hydroxy 21 acetyloxy-A5 0 pregnadiene white crystalline dl-3,20-diketo-9u-bromo 16fl-chloro-1 113, 17a-dihydroxy-2l-acetyloxy-M-pregnene is obtained.

dl 3,20 diketo 911:,165 dichloro 11 3,1701 dihydroxy-2l-acetyloxy-M-pregnene may be prepared by admixing the 9a-bromo-11fi-hydroxy compound (i. e. the product of Example VII) with a small amount of potassium acetate and boiling the mix in alcohol to effect formation of the 911,l6-17 dioxido derivative, the dioxido compound so obtained upon reacting with hydrochloric acid in chloroform at about 5 C. yields dl- 3,20 diketo 901,165 dichloro 1113,17m dihydroxy- 2l-acetyloxy-A -pregnene. Similarly the individual optically active isomers of 3,20 diketo 90:,1619 dihalo 1113,1711 dihydroxy 21- acetyloxy-A -pregnene, e. g. the natural modification of 3,20 diketo 9u,16}9 dibromo 115,17 dihydroxy- 2l-acetyloxy-A -pregnene are obtained from the appro priate optically active 3,20-diketo-16fl-halo-17a-hydroxy" 21acetyloxy-A -pregnadiene.

The next step in the process of this invention is the oxidation of the ll-hydroxy substituent of Compound VIII of the foregoing schematic diagram to produce the 16 halo 17 hydroxy 17 (acyloxyacetyl) cyclopentano 9 halo 10,13 dimethyl A dodecahydrophenanthren 3,11 dione (Compound IX) THalogen Example VIII To an agitated complex of chromium trioxide and pyridine prepared in the cold by admixing 50 parts by weight of chromium trioxide with 500 parts by weight of pyridine is added substantially 50 parts by weight of dl-3,20-diketo- 9,16 dibromo 1113,1711 dihydroxy 21 acetyloxy- A pregnene in approximately 800 parts by weight of pyridine while maintaining the temperature at about 10 C. The mixture so obtained is permitted to stand at room temperature for about 16 hours with occasional agitation. The mixture is then filtered and the residue washed with pyridine. The pyridine wash and the original filtrate are combined and the solution so formed is poured into five times its Weight of water and the composite extracted with chloroform. The extracts are combined and cooled to about 0 C. The cooled solution is then washed with dilute hydrochloric acid and then with water. The organic layer is recovered, dried, and evaporated to dryness. The residue is white crystalline dl 3,11,20 triketo 9u,16[3- dibromo 17m hydroxy 21 acetyloxy A pregnene.

Replacing a l-3,20 diketo 91:,165 dibromo 11,6,17adihydroxy 21 acetyloxy A pregnene in Example VIII with an equal weight of al 3,20 diketo 901,166- dichloro 1113,17a dihydroxy 21 acetyloxy A pregnene and subjecting same to the series of steps set forth in Example VIII dl 3,11,20 triketo 91:,16/3-dichloro 17a hydroxy 21 acetyloxy A pregnene is obtained.

In a similar fashion the individual optically active isomers of 3,11,20 triketo 911,16 dihalo 17cc hydroxy 21 acetyloxy A pregnene, e. g. the natural modification of 3,11,20 triketo :,165 dibromo 17ahydroxy 21 acetyloxy A pregnene is obtained from the appropriate optically active 3,20 diketo 904,165- dihalo- 1 1B, 1 7u-dihydroxy-2 l-acetyloxy-A -pregnene.

The next step in the process of this invention is the removal of the 9 halogen and 16 halogen substituents of the 16 halo 17 hydroxy 17 (acyloxyacetyl)- cyclopentano 9 halo 10,13 dimethyl A dodecahydrophenanthren 3,11 dione. In this step the halogen substituent in the 9 position is removed first to provide a 16 halo 17 hydroxy 17 (acyloxyacetyl)- cyclopentano 10,13 dimethyl A dodecahydrophenanthren 3,11 dione (Compound X which compound upon dehalogenating produces a 17 hydroxy 17- (acyloxyacetyl) cyclopentano 10,13 dimethyl A dodecahydrophenanthren 3,11 dione (Compound XI). It is preferred to remove both halogen substituents in one operation and as illustrative of this employing a large excess of Raney nickel is the following:

Example IX To a suitable reaction vessel containing 20 parts by weight of Raney nickel, approximately 200 parts by weight of acetone and about 20 parts by weight of water is added approximately 3.5 parts by weight of dl 3,11,20 triketo- 911,165 dibromo 17a hydroxy 21 acetyloxy A pregnene and the mixture so obtained refluxed in an atmosphere of nitrogen for about 4 hours. The reaction mix is then filtered and the residue washed with warm acetone. The washings and original filtrate are combined and subjected to vacuum distillation. The residue is then taken up with chloroform and the solution so formed washed with water and dried. The dried solution is then subjected to vacuum distillation whereupon there is obtained white crystalline dl 3,11,20 triketo 17a hydroxy 21 acetyloxy A pregnene (M. P. 240243 C.) which compound is identical with the acetate of racemic (dl) cortisone.

Similarly the individual optically active isomers such as the natural modification (dextro-rotatory form) of 3,11,20 triketo 17a hydroxy 21 acetyloxy A pregnene are obtained beginning with the appropriate optically active isomers of 3,11,20 triketo 911,165 dibrorno 17cc hydroxy 21 acetyloxy A pregnene. The 21 acyl derivative of the natural modification of 3,11,20 triketo 17 x,21 dihydroxy A pregnene according to infrared spectrum, melting point and optical rotation is identical with the corresponding acyl derivative of natural cortisone. Thusly, it is to be understood that the optically active isomers referred to hereinbefore as the natural modification are those which through the course of reactions as afore schematically outlined starting with the dextro-rotatory form of 3 keto 17 formyl- M androstatriene provide for the acyl derivatives of natural cortisone.

While as aforedescribed the 16 halo l7 hydroxy- 17 (acyloxyacetyl) cyclopentano 10,13 dimethyl- A decahydrophenanthren 3 one compound (Compound VII) was employed to prepare the 9 halo- 11 hydroxy addition product (Compound VIII) it has been found that it (i. e. Compound VII) upon dehalogenating provides for a 17 hydroxy 17 (acyloxyacetyl) cyclopentano 10,13 dimethyl 11 decahydrophenanthren 3 one which compound upon reacting with a hypohalous acid produces a 9 halo l1 hydroxy addition product which addition product upon dehalogenating yields a 11,17 dihydroxy 17 (acyloxyacetyl) cyclopentano 10,13 dimethyl A dodecahydrophenanthren 3 one. This sequence of steps is 9 outlined schematically as follows, R and .1: having the same significance as aforedescribed.

CH: O R CH|O R -orr CHOR OHIOR As illustrative these steps proceeding from Compound VII to Compounds XII and XIII and finally to Compound XIV is the following:

Example X To a suitable reaction vessel containing parts by weight of Raney nickel, approximately 100 parts by weight of acetone and about 10 parts by weight of water is added and intimately mixed 3 parts by weight of di- 3,20 diketo 16p bromo 17a hydroxy 21 acetyloxy-A -pregnadiene and the mixture so obtained refluxed in an atmosphere of nitrogen for about 4 hours. The reaction mix is then filtered and the residue washed with warm acetone. The washings and original filtrate are combined and subjected to vacuum distillation. The residue-is then taken up with chloroform and the solution so formed washed with water and dried. The dried solution is then subjected to vacuum distillation whereupon there is obtained white crystalline dl-3,20-diketol7a-hydroxy-2l-acetyloxy-A -pregnadiene.

Similarly the individual optically active isomers such as the natural modification of 3,20-diketo-17a-hydroxy- 2l-acetyloxy-A -pregnadiene are obtained beginning with the appropriate optically active isomer of 3,20-diketo- 16p bromo 17oz hydroxy 21 acetyloxy A pregnadiene. The natural modification or dextro-rotatory form of 3,ZO-diketo-17a-hydroxy-2l-acetyloxy-A pregnadiene possesses a melting point of 233236 C.

The aforedescribed dl-3,20-diketo-17a-hydroxy-21-acetyloxy-A -pregnadiene upon reacting with a hypohalous acid such as hypobromous acid in accordance with the process of Example VII produces white crystalline dl 3,20 diketo 9a bromo 11fi,17u dihydroxy 21- acetyloxy-A pregnene which 9-bromo-11-hydroxy addition product upon dehalogenating using Raney nickel provides for dl 3,20 diketo 115,170: dihydroxy 21- acetyloxy-M-pregnene which compound has the same infrared spectrum as the (21-) acetate of 17-hydroxy-corticosterone. Similarly but beginning with the natural modification of 3,20 diketo 17a hydroxy 21 acetyloxy- A -pregnadiene the acetate obtained is identical with the (21-) acetate of l7-hydroxy-corticosterone.

While this invention has been described with respect to certain embodiments it is not so limited and it is to be understood that modifications and variations obvious to those skilled in the art may be made without departing from the spirit or scope of this invention.

ADDENDUM The natural modification of 3-keto-16,17-oxido-17- formyl-A -androstadiene referred to on page 5, lines 17 it, is a white crystalline substance melting at 193- 197 C. The natural modification of 3-keto-16,17-oxidol7-carboxy-A*- -androstadiene referred to on page 7, lines 1 fi., is a white crystalline substance melting at 211- 212 C. The natural modification of 3,20-diketo-16,17- oxido-21-diazo-A -pregnadiene referred to on page 9, lines 5 ii, is a yellow crystalline substance melting at 165168 C. The natural modification of 3,20-diketo- 16,6 bromo 17oz hydroxy 21 acetyloxy A pregnadiene referred to on page 11, lines 16 ii, is a white crystalline substance melting at 146-148" C.

What is claimed is:

1. 16,17 oxido 17 carboxy cyclopentano 10,13- dimethyl-A -decahydrophenanthren-3-one 2. The acid chloride of 16,17-oxido-17-carboxy-cyclopentano 10,13 dimethyl A4301) decahydrophenanthren-3-one of the structural formula References Cited in the file of this patent UNITED STATES PATENTS 2,648,663 Julian Aug. 11, 1953 2,656,349 Ruzicka Oct. 20, 1953 2,659,743 Murray Nov. 17, 1953 2,659,744 Schneider Nov. 17, 1953 

1. 16,17-OXIDO-17-CARBOXY-CYCLOPENTANO-10,13DIMETHY-$4,9(11) -DECAHYDROPHENANTHREN-3-ONE 